Gastric cancer comprises only 2% of cancer cases in the United
States but represents the most prevalent cancer in less developed
countries and the fourth most prevalent cancer world wide. Early
diagnosis and therapeutic intervention could radically reduce the number
of deaths attributed to this disease. For this reason, minimally
invasive cancer specific tests are urgently sought and recently have
included the serological tumor markers. The objective of this study was
to compare ten tumor antigens (carcinoembryonic antigen [CEA], CA 19-9,
CA 195, CA 50, CA 72-4, CA 125, CA 15-3, CA 27.29, alpha-fetoprotein
[AFP], and Cyfra 21-1) for their diagnostic efficacy in gastric cancer
patients. The assays used in this study included CA 72-4, CA 19-9, CA
15-3, CA 125, CA 27.29, and Cyfra 21-1 from Fujirebio
Diagnostics/Centocor Inc., CA 195 and CEA from Hybritech, Inc., CA 50
from CIS bio international, and AFP from Abbott Inc. Sera from 200
healthy adults were used to determine the normal reference intervals.
Diagnos tic parameters were determined using sera from 554 patients
including 184 with no disease, 11 with non-malignant disease, 12 with
gastric cancer, and 347 with other types of cancer. The diagnostic
sensitivities included: CA 50 (70%), CA 19-9 (64%), CA 195 (58%), CEA
(50%), CA15-3 (45%), CA 125 (40%), CA 27.29 (30%), CA 72-4 (27%), AFP
(22%), and Cyfra 21-1 (9%). With the exception of CA 195 and CA 15-3
(75% specificity), all the markers had diagnostic specificities equal to
or greater than 80% (range 80-95%). Analytical parameters were evaluated
for the assays and compared favorably We concluded that CA 50 was the
best tumor antigen for use in the diagnosis of gastric cancer.

With 558,458 estimated new cases and 405,215 estimated deaths
world-wide in 2001, gastric cancer is the fourth most prevalent cancer
globally. Similarly, in less developed countries gastric cancer ranks
first in prevalence and second only to lung cancer for incidence of new
cases (World Health Organization, 2001). Originally the number one cause
of cancer deaths in the United States, today the incidence and
prevalence of gastric cancer have declined drastically, possibly due to
the widespread use of refrigeration and antibiotics in the processing of
food. This has led to a decreased consumption of salt cured and smoke
cured meat and fish which have long been associated with increased risk
of gastric cancer (Hossfeld and Sherman, 1990; Key et al., 1998).
Additionally, Helicobacter pylori infection is considered to be a
predisposing factor for gastric cancer because it can cause chronic
atrophic gastritis, resulting in increased gastric pH, bacterial
colonization of the stomach, and the production of carcinoge nic
N-nitroso compounds from dietary proteins. The decreased incidence of
Helicobacter pylori infection in the United States, due to improved
sanitation and the use of antibiotics, has paralleled the observed
decline in gastric cancer. No comparable decreases of infection rates or
gastric cancer incidences have been observed in less developed
countries. (Key et al., 1998).

Possible therapeutic methods and strategies include total
gastrectomy, radical subtotal gastrectomy, resectioning of involved
portions of liver, pancreas, and transverse colon, splenectomy and
removal of involved lymph nodes, chemotherapy, and radiotherapy
(Hossfeld and Sherman, 1990; National Cancer Institute Symptoms, 2000).
The prognosis depends on the extent of tumor spread at the time of
initial treatment and is generally better for gastric lymphomas than for
carcinomas. The overall five-year survival rate for all patients is
approximately 10%. This increases to about 40% for patients who were
diagnosed and treated early (Hossfeld and Sherman, 1990; National Cancer
Institute Symptoms, 2000).

Traditional methods of gastric cancer diagnosis have included
biopsy, barium X-rays, gastroscopy, upper GI series with double contrast
media, computer tomography (CAT scans), exfoliative cytology, and
gastric cytology following brushing and washing of the stomach (National
Cancer Institute Symptoms, 2000; Hossfeld and Sherman, 1990). There is
evidence to support the use of serum tumor antigens as an aid in
diagnosis, to measure tumor size, and to evaluate post surgical
therapeutic methods and the presence of recurrent disease in gastric and
other gastrointestinal cancers. (Wu and Nakamura, 1997). CA 72-4 is the
principal tumor antigen in current use for the diagnosis and prognosis
of gastric cancer. Other markers which have been assessed for gastric
cancer include, among others, CA 19-9, CA 50 and CEA, (Wu and Nakamura,
1997). Similarly CAl95 and CA125 have been reported to have some
sensitivity for gastric cancer (Hall et al., 1999). CA 19-9, CA 50, and
CA195 are markers for a variety of gastrointestinal ca ncers and CA125
is a marker of ovarian cancer. Elevated CA 15-3 has been reported in a
variety of adenocarcinomas including breast, lung, ovary, colon, and
pancreas. It is principally used in the assessment of breast cancer
patients (Lauro et al., 1999). CA27.29 is used as a marker for
therapeutic monitoring in breast cancer patients and has not been
reported in gastric cancer patients (Gion and Minone, 2001; Frenette et
al., 1994). It has been reported in some cases of ovarian, uterine,
lung, prostate, colorectal, and pancreatic cancer (Fujirebio
Diagnostics, 1998). Elevated alpha-fetoprotein has been extensively used
as a marker for hepatic disease, including hepatoma, and for yolk sac derived germ cell tumors. It has also been reported in a few patients
with other gastrointestinal cancers (Wu and Nakamura, 1997; Butch et
al., 2000). Similarly, Cyfra 21-1 is used as a marker of lung cancer and
has not been reported to be useful in diagnosis and monitoring of
gastric cancer (Wu and Nakamura, 1997; Hubbard, 1 990).

CA 72-4 is a 1 million kDa mucin-like glycoprotein complex (TAG 72)
which is predominantly associated with human adenocarcinoma of the
gastrointestinal tract (Johnson et al., 1986; Lan et al., 1987). Two
monoclonal antibodies (cc49 and B72.3) have been developed against CA
72-4 (TAG 72) which detect distinct antigenic determinants expressed on
the circulating antigen found in a variety of gastrointestinal cancers,
and lung cancer (Patterson et al., 1986; Klug et al., 1986). The use of
CA 72-4 is recommended in cases of gastric cancer and it has been used
in tumor panels (ratio of CAl9-9 to CA72.4) to exclude pancreatic
disease (Wu and Nakamura, 1997).

CA 19-9 is a high molecular weight (200-1000 kDa) mucin like
glycoprotein which exists as a ganglioside on tumor cells. The
expression of this sialylated [Le.sup.a] blood group antigen (sialylated
lactoN-fucopentoeose II ganglioside) is required for the expression of
CA 19-9 and hence [Lea.sup.a-b-] patients do not express the antigen and
can present as false negatives (Steinberg, 1990). A monoclonal antibody was developed against CA 19-9 derived from the SW-1116 human colon
carcinoma cell line (Koprowski et al., 1979). CA 19-9 is clinically
useful in the detection of pancreatic, colorectal, hepatic, and other
gastrointestinal cancers. It has also been described in breast and lung
cancer (Wu and Nakamura, 1997). CA 50 is related to CA 19-9 but lacks a
fucose residue. Its epitope is the same as that found in [Le.sup.a-b-]
(Lewis negative) patients. It has been reported in patients with
gastric, colon, and hepatic cancer (Wu, 1996). CA 195 is also related to
CA 19-9. It is defined by the mouse monoclonal antib ody CC3C-195 and it
recognizes both [Le.sup.a] and sialyl-[Le.sup.a] epitopes. Binding with
higher affinity to the sialylated [Le.sup.a] blood group antigen, the
antibody can bind to both the sialylated and unsialylated [Le.sup.a]
blood group. CA 195 has been reported in pancreatic, colon, and gastric
cancers (Wu and Nakamura, 1997).

CA 125 is a 200 kDa glycoprotein expressed by tissue of mullerian
duct origin as well as by ovarian tumors. It is defined by the mouse
monoclonal antibody OC 125 derived from an ovarian cancer cell line
(OVCA 433). It is currently used for detecting epithelial tumors of the
ovary. However, it has also been reported in breast, lung, endometrial,
and gastrointestinal tumors. It can be elevated with pregnancy and with
pelvic inflammatory disease. (Jacobs and Bast, 1989)

CEA is a 150-300 kDa cell surface heterogeneous glycoprotein which
is structurally similar to IgG. Abnormally elevated serum levels have
been reported in patients with colorectal cancer, breast cancer, and a
variety of other carcinomas (Cooper et al., 1979; Reynoso et al., 1972).
Additionally, CEA levels can be elevated in heavy smokers and patients
with nonmalignant pathologies (Clarke et al., 1982). Consequently, CEA
is currently used in therapeutic monitoring and as a diagnostic aid, but
is not useful in screening for cancer.

CA 27.29 is a mucin antigen defined by the monoclonal antibody
B27.29. This antibody recognizes an antigen extracted from ascites fluid
derived from patients with breast cancer. CA 27.29 has an epitope that
is shared with the DF3 antibody of CA 15-3. (Burtis and Ashwood, 1996).
It is currently being marketed as a specific test for breast cancer.

Alpha-fetoprotein (AFP) is a 70,000 kDa glycoprotein which has been
isolated from patients with hepatocellular carcinomas and germ cell
tumors (Chan et al., 1986). Maternal serum and amniotic fluid APP levels
are routinely used for the prenatal diagnosis of open neural tube disease and gastroschisis, and together with karyotyping have been used
to diagnose cases of Down's syndrome (Milunsky, 1987; Knight et
al., 1988). Alpha-fetoprotein has been reported to be useful in
screening for hepatocellular carcinoma in high incidence areas such as
Asia, and for classifying and staging germ cell tumors (Chan et al.,
1986). Alpha-fetoprotein has been reported in cases of hepatocellular
carcinoma, testicular and ovarian germ cell tumors, as well as
pancreatic, colorectal, and gastric carcinomas (Butch et al., 2000).

Cyfra 21-1 is a 40 kDa fragment derived from cytokeratin 19. One
subgroup of intermediate filament proteins, cytokeratins are found in
epithelial cells. The monoclonal antibody recognizes an epitope on the
Cyfra 21-1 fragment and is useful in the detection of non-small cell
lung cancer, including squamous cell carcinoma of the lung (Pujol et
al., 1993). It has also been reported in cases of cervical cancer and
other malignancies (Bonfrer et al., 1994; Bodenmuller et al., 1992).

In a clinical laboratory, in order to compare different assay
methods one must evaluate their specific performance characteristics
(precision, linearity, analytical sensitivity, and analytical
specificity) and their clinical performance (normal reference interval
and predictive values). Precision is evaluated by assaying replicate
samples and determining the mean, standard deviation, and coefficient of
variation. Linearity is determined by assaying dilutions of an elevated
serum sample and plotting the results and/or performing regression
analysis. The minimum detectable concentration of analyte in the test
(analytical sensitivity) is determined by assaying replicate samples
lacking the analyte (e.g., diluent) and calculating the mean plus two
standard deviations. Values falling below this cutoff are presumed to be
analyte free. The analytical specificity represents the degree of assay
interference from drugs or other chemicals (e.g., bilirubin) present in
the specimen. This is not always reported but can be determined by
spiking samples with varying concentrations of the suspected interfering
drugs/chemicals.

In order to establish a healthy (normal) adult reference interval
for the analyte using a particular assay, one calculates the mean plus
or minus two standard deviations (95% confidence interval) on assay
results from a population set of adults known to be in good health.
Subsequently, any patient result which falls within this interval is
considered to be "normal" or healthy; whereas, patient results
which fall outside (above or below) the limits of this interval are
considered to be abnormally elevated or decreased respectively. For
tumor markers a low result would have no clinical significance.
Therefore, one establishes the cutoff between normal (presumed negative
for disease) and abnormal (presumed positive for disease) results by
using the mean plus two standard deviations. Predictive validity
compares the ability of a new test method to accurately diagnose/predict
the presence or absence of disease with that of an established method.
Predictive value results include diagnostic sensitivity and specific
ity, diagnostic efficiency, and positive and negative predictive values.
For the calculation of predictive values, one compares the test results
with the "true results" as defined by an external test method
considered to be the reference test method. For example one could
compare the results of a tumor antigen assay (test results) with those
obtained by the physician with histologic analysis of biopsy material
(true results). Individual patient assay results are then assigned to
one of four categories (true positives [TP], true negatives [TN], false
positives [FP], or false negatives [FN]) from which the predictive
values are derived. Predictive values include: (a) diagnostic
sensitivity (% of individuals with the disease who test positive by the
assay), i.e., [100 TP/(TP + FN)], (b) diagnostic specificity (% of
individuals without the disease who test negative by the assay), i.e.,
[100 TN/(TN + FP)], (c) diagnostic efficiency (% of all test results
that are either true positives or true negatives), i.e., [10 0 (TP +
TN)/(TP + TN + FP + FN)], (d) positive predictive value (% of all
positive test results that are true positives), i.e., [100 TP/(TP +
FP)], and (e) negative predictive value (% of all negative test results
that are true negatives), i.e., [100 TN/(TN + FN)].

The purpose of this study was to evaluate the analytical and
clinical performances often serologic tumor marker tests (CEA, CA 19-9,
CA 195, CA 50, CA 72-4, CA 125, CA15-3, CA 27.29, AFP, and Cyfra 21-1)
for the detection of gastric cancer. Particular attention was paid to
the comparison of their diagnostic sensitivities as this value reflects
the tumor marker test's ability to detect the disease. A working
hypothesis that CA 72-4 would prove to be superior to the other tumor
markers was developed based on reports in the literature of its
superiority (Wu and Nakamura, 1997; Spila et al., 1996).

MATERIALS AND METHODS

Assays--All assays were performed according to the directions
supplied by the manufacturers. The [Tandem.sup.R]-E CEA assay
(Hybritech, Inc) is a solid phase two-site immunoenzymometric assay
(ELIZA) utilizing two monoclonal IgG antibodies directed against unique
sites on the CEA antigen. This assay was quantitated
spectrophotometrically using the Photon Immunoassay Analyzer[TM] from
Hybritech, Inc. The [Tandem.sup.R]- CA 195/Hybri C Mark[TM] assay
(Hybritch Europe, Inc.) is a solid phase two-site immunoradiometric
assay (CA 195) (RIA) utilizing monoclonal IgM antibodies developed
against the Lewis A (blood group determinant) and sialyated Lewis A
epitopes on the CA 195 antigen. This assay was measured using a
Genesys[TM] 5000 gamma counter (Laboratory Technologies, Inc.). The
Cento[cor.sup.R] CA l9-9[TM] assay (Fujirebio Diagnostics,
Inc./Centocor, Inc.) is a solid phase radioimmunoassay (CA 19-9) (RIA)
using the 1116-NS-19-9 antibody for both the capture and tracer
antibodies. This antibody is directed aga inst an epitope which is
biochemically related to the Lewis A determinant; the assay was
quantitated using a Genesys[TM] 5000 gamma counter (Laboratory
Technologies, Inc.). The RIA-[gnost.sup.R] CA-50 assay (CIS bio
international) is a solid phase two-site immunoradiometric assay (CA 50)
(RIA) utilizing monoclonal mouse antibodies directed at two carbohydrate
chains (sialylated Lewis A and sialylated lactotetraose) of the
adenocarcinoma cell line Cob 205. The assay was measured using a
Genesys[TM] 5000 gamma counter (Laboratory Technologies, Inc.). The
[Centocor.sup.R] CA 72-4[TM} assay (Fujirebio Diagnostics,
Inc./Centocor, Inc.) is a solid phase radioimmunoassay (CA 72-4) (RIA)
based on two monoclonal antibodies, cc49 and B72.3, which react with
distinct antigenic determinants on a tumor associated glycoprotein TAG
72. The antigen was quantitated using the Genesys[TM] 5000 gamma counter
(Laboratory Technologies, Inc.). The [Centocor.sup.R] CA l25[TM] assay
(Fujirebio Diagnostics, Inc./Centocor, Inc.) is a s olid phase two-site
immunoradiometric assay (CA 125) (RIA) using two mouse monoclonal
antibodies, 0C125 directed against the OVCA 433 ovarian cancer cell line
and a second antibody directed against another CA 125 epitope. The assay
was measured using a Genesys[TM] 5000 gamma counter (Laboratory
Technologies, Inc.). The [Centocor.sup.R] Cyfra[TM] 21-1 assay
(Fujirebio Diagnostics, Inc./Centocor, Inc.) is a solid phase
immunoradiometric assay (RIA) utilizing two mouse monoclonal antibodies,
KS19.1 and BM19.21, to detect cytokeratin 19 fragments in serum. The
assay was quantitated using a Genesys[TM] 5000 gamma counter (Laboratory
Technologies, Inc.). The [Centoco.sup.R] CA [15-3.sup.R] assay
(Fujirebio Diagnostics, Inc./Centocor, Inc.) is a solid phase
radioimmunoassay (RIA) using the 11 5D8 murine monoclonal antibody as
the capture antibody and the [I.sup.125] labeled DF3 murine monoclonal
antibody as the tracer. This assay was quantitated using an Iso
[Data.sup.R] gamma counter. The [Truquant.sup.R] BR[TM] as say
(Fujirebio Diagnostics, Inc./Centocor, Inc.) is a solid phase
competitive inhibition radioimmunoassay (competitive RIA) using
polystyrene tubes coated with CA 27.29 antigen and [I.sup.125] labeled
murine monoclonal B27.29 antibody. This assay was quantitated using an
Iso [Data.sup.R] gamma counter. The [IMx.sup.R] APP assay (Abbott
Laboratories, Inc.) is a microparticle enzyme immunoassay (MEIA)
utilizing two monoclonal antibodies directed against unique sites on the
AFP antigen. This assay was quantitated using the [IMx.sup.R] Automated
Analyzer from Abbott Laboratories, Inc. All dilutions were performed
using diluent supplied by the manufacturers in the assay kits. These
diluents contain physiological concentrations of protein which maintains
the sample protein concentration within limits which do not affect the
assay. Regression analysis was used to determine the linearity of the
assays and the independent t-test was used to compare male and female
subjects when developing the reference intervals. Stat istical analysis
was performed using SPSS software.

Patients--Procedures used in this study were in accord with ethical
standards established by the University of Southern Mississippi (USM).
Permission for the study was granted by the USM Human Subjects
Protection Review Committee (HSPRC/IRB).

All study participants were selected from patients seen in an area
hospital. Five hundred and fifty four patients were randomly chosen and
the assays were run in a blind fashion. Blood samples were collected
using appropriate aseptic technique. Following serum separation aliquots
were coded and frozen at -20[degrees]C. Subsequently, aliquots were
thawed at 37[degrees]C and assayed in duplicate (sample permitting) for
the tumor antigens. The diagnoses were obtained from the attending
physicians and were based on pathological examination. Patient
Classifications included (a) no known disease, (b) nonmalignant disease,
(c) non gastric cancer, and (d) gastric cancer. Cancer patients were
classified according to the primary site of the tumor, regardless of the
presence or absence of metastases. Since available information on
patient therapy was incomplete, statistical analyses were performed on
the total patient pool without reference to this.

The normal control subjects were healthy males (100) and females
(100) ranging from 18-65 years of age. Their blood samples were
collected and processed in the same manner as the patient samples.

RESULTS

Precision and Linearity--Quality control samples analyzed over a 6
month period were used to determine intra- and inter-assay precision.
The within-run coefficient of variation (%CV) was less than 10% for all
but the CA 15-3 assay which was somewhat higher (20%) (Table 1).
Similarly the between-run coefficient of variation was less than 17% for
each of the assays (Table 2). Serial dilutions of abnormal pool samples
exhibited good linearity (Fig. 1) with [R.sup.2] values equal to or
greater than 0.989 for all the assays.

Reference Intervals--The minimum detectable concentration was
determined by analyzing approximately 20 replicates of the zero
calibrator/diluent and establishing the mean + 2SD as the cut-off value
(Table 3 a). The normal adult reference intervals were established by
determining the 95% confidence intervals for healthy control male and
female subjects. The intervals (Tables 3a, 3b) were broader than those
reported by the manufacturer for all but the CA 125, CA 72-4, CA 27.29,
and AFP assays which were somewhat narrower. There was no significant
difference between healthy adult males and females for any of the assays
except CA 19-9, where the males were significantly (p <0.05) higher.

Diagnostic Parameters--In this study there were 184 patients
without disease, 11 patients with nonmalignant disease, 12 patients with
gastric cancer, and 347 patients with other types of cancer including:
pancreatic, small intestinal, esophageal, lung, breast, ovarian,
prostatic, renal, colorectal, gallbladder, hepatic, cecal, uterine,
testicular, head and neck, leukemia, lymphoma, and all other types.
Patients' diagnoses were made by the attending physicians and were
predicated on a variety of pathologic findings including the histologic
analysis of biopsy or surgical tissue. For purposes of this study,
patients with gastric cancer were considered to be positive for disease.
Similarly, cutoffs between normal (negative) and abnormal (positive)
test results used were those listed by the manufacturers and are cited
in Table 4. In Table 4, the diagnostic sensitivity of CA 50 (70.0%) is
superior to that of the other markers (CA 19-9, 63.6%; CA 195, 58.3%;
CEA, 50.0%; CA 15-3, 45.5%; CA 125, 40.0%; CA 27.29, 30.0 %; CA 72-4,
27.3%; AFP, 22.2%; and Cyfra 21-1, 9.1%). The diagnostic specificities
of the ten assays range from 75-95% with Cyfra 21-1 having the highest
value. The negative predictive and positive predictive values range from
97-99% and 3-9% respectively. The efficiency of the Cyfra 21-1 assay was
the best (92.6%), presumably due to the fact that it had the highest %
specificity.

DISCUSSION

The incidence and prevalence of gastric cancer make it an important
medical problem world wide. For some time the medical community has
sought a minimally invasive, inexpensive, and early diagnostic test for
this and other types of cancer. With the exception of PSA in prostate
cancer, tumor markers have generally not proven useful as screening
tests either because their incidence is too low in the general public,
or because the cutoff between benign and malignant disease is not
sufficiently precise. Thus increased concentrations have been reported
in some cases of benign disease while not observed in cases of in situ cancer when the prognosis is best (Wu and Nakamura, 1997; Roulston and
Leonard, 1993). Despite this, many tumor antigens have proven useful for
diagnosis and for therapeutic monitoring and the detection of recurrent
disease.

In this study we compared ten serologic assays (CEA, CA 19-9, CA
195, CA 50, CA 72-4, CA 125, CA 15-3, CA 27.29, AFP, and Cyfra 21-1) for
their efficacy at detecting gastric cancer. The within-run and
between-run precision was slightly higher for CA 15-3 and CA 195 than
for the other assays, but all values were below 20%. The linearity was
excellent for all the assays. The minimum detectable concentration of
analyte (zero calibrator/diluent mean + 2SD) was slightly higher for CA
125 than for the other assays. This test was therefore repeated using a
patient sample that had previously given a result of 0 U/mL (data not
shown). The results did not differ from those of the zero
calibrator/diluent, confirming its value. The normal reference intervals
were broader than those cited by the manufacturers for all the assays
except CA 125, CA 72-4, CA 27.29, and AFP. The CA 19-9 assay exhibited a
significantly higher reference interval for males than for females;
otherwise there were no significant differences between the sexes. The
assays compared favorably for cost and availability of instrumentation.
With the exception of CEA and AFP, all of the assays were radiolabeled
([I.sup.125]) and therefore had shorter shelflives. The turnaround time varied from 1 hour for AFP (automated assay) to approximately 3-24 hours
for the other assays (manual assays with varying incubations periods).
The CEA (ELIZA assay) required only the use of a spectrophotometer and
therefore might be more attractive than the other assays for use in a
small lab.

Sera from 554 patients seen in a local hospital were assayed for
ten tumor antigens and the diagnostic parameters were compared. The
physicians' diagnoses and the manufacturers suggested cutoff values
were utilized to assign the test results to the categories of true or
false positives and negatives. Predictive values were calculated for
gastric cancer. The most important finding of this study was the
observation that CA 50 was clearly superior to CA 72-4 for the detection
of gastric cancer, exhibiting a diagnostic sensitivity of 70% as
compared to 27%. Similarly, CA 19-9, CA 195, CEA, CA 15-3, and CA 125
all excelled when compared to CA 72-4. The importance of this stems from
the fact that CA 72-4 has been reported to be the best tumor marker for
gastric cancer and is currently being marketed as a
gastric/gastrointestinal cancer marker. Since CA 50, CA 195, and CA19-9
share very similar epitopes, it should not be surprising that all three
react similarly with gastric as well as with other carcinomas.
Similarly, CEA shares some antigenic determinants with CA 19-9 (Wu and
Nakamura, 1997).

In a similar study, Pectasides et al. (1997), found CA 50 and CA
19-9 to be superior to CEA for the diagnosis of gastric cancer. Haglund
et al. (1992) investigated CA 19-9 and CA 50 for their diagnostic
capabilities and found them to have the same sensitivity for gastric
cancer.

In two studies the authors reported a discrepancy between the
markers depending on the stage of the cancer. In a study involving 100
cancer patients (44 with early cancer and 56 with advanced cancer),
Kodama et al. (1995) reported that in advanced cancer CA 72-4 was
superior to CEA and CA 19-9 for the diagnosis, prognosis, and detection
of recurrent disease. By contrast they found CA 19-9 and CEA to be
better for the detection of early stage (I and II) disease. Likewise, in
a study by Van-Dalen and Kessler (1996) in which 4266 serum samples from
23 labs were analyzed for CEA, CA 15-3, CA 19-9, CA 72-4, CA 125, Cyfra
21-1, and AFP, the authors reported that CA 72-4 was the most sensitive
for stage IV disease. However, the authors found CA 72-4, CA 19-9, and
CEA to be equally sensitive for stage I-III disease.

By contrast, in a study of 242 patients, Spila et al. (1996) found
that CA 72-4 was superior to both CEA and CA 19-9 for the diagnosis and
prognosis of both primary and recurrent gastric cancer. Likewise,
Fernandez-Fernandez et al. (1996) have reported that in a study of 167
patients with gastric cancer and 92 patients with benign disease they
found CA 72-4 to be superior to both CA 19-9 and CEA at all stages of
disease. Discrepancies between their results and ours could be the
result of genetic differences in the patient populations, the stage of
the tumors, the presence of pathologic complications, the prevalence of
disease (gastric cancer) in the population sample, and/or the use and
type(s) of therapies. Since CA 199, CA 195, CA 50, and CA 72-4 are blood
group antigen type carbohydrate markers and CEA contains incomplete
blood group substances, it is not surprising that patients who do not
express a particular blood group antigen will have serum which does not
react in tumor marker assays that use monoclo nal antibodies directed at
epitopes found on these antigens (Wu and Nakamura, 1997). Thus the
genetic background of a patient could cause false negative values with
these tests. The greater the tumor burden and the more metastatic it has
become, the greater the likelihood of increased levels of antigen and
hence of positivity with a particular antigen assay. Both positive and
negative predictive values are somewhat dependent on the disease
prevalence in the sample population (Cembrowski et al., 2000). For this
reason many studies are designed to include increased numbers of
patients with the disease being studied (high prevalence), and to
exclude any patients with other diseases. While this would lead to
better (higher) predictive values, it doesn't reflect the local
patient population. In this study, patients were randomly selected and
included therefore only 12 gastric cancer patients and numerous patients
with other types of cancer and with no cancer. This better represents
what is actually seen in America n hospitals but could introduce a bias
if the disease cohort shares some unique feature(s). The gastric cancer
patients' sera were collected prior to surgery and chemotherapy but
there is limited data about any medications they may have been using
which could have interfered with the assay. Regretfully that information
is not available at this time.

In conclusion, ten assays (CEA, CA 19-9, CA 195, CA 50, CA 72-4, CA
125, CA 15-3, CA 27.29, AFP and Cyfra 21-1) were evaluated for their
efficacy at diagnosing gastric cancer. CA 50 proved to be superior to
the other assays with CA 19-9, CA 195, and CEA also proving effective.
In contrast to previous studies, our results did not support the use of
CA 72-4 for the diagnosis of gastric cancer and therefore our hypothesis
was rejected.

Clarke, C.A., T.P. Whitehead, and A.G.W Whitfield. 1982.
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Cooper, M.J., C.R. Mackie, D.B. Skinner, and A.R. Moossa. 1979. A
reappraisal of the value of carcinoembryonic antigen in the management
of patients with various neoplasms. British J. Surg. 66:120-123.